In the next decade, breast cancer screening will likely be some combination of x-ray, ultrasound (US) and/or optical imaging, if this combination can be performed efficiently. Towards this goal, a proof-of-concept multimodality system is proposed in which, x-ray, US and optical breast images are all acquired in the same mammographic geometry, making it possible to directly compare the complex patterns of the US and optical images with those patterns in a 3D version of mammography, digital tomosynthesis mammography (DTM), where there is, from its similarity with mammography, a great wealth of experience. It is hypothesized that with this system, not only will it be possible to reap the direct benefits of mammographic/US/optical co-localization but also to achieve superior image quality and diagnostic information from the combination of these modes. Spectroscopic photoacoustic tomography (S-PAT) is a promising imaging approach, with contrast provided by red and near infrared light absorption and with high resolution and sensitivity provided by the thermoacoustic signal detection from US transducers. These transducers will be specialized, broadband arrays allowing for synthetic aperture formation. Further enhancing sensitivity will be the short optical path lengths from both, compressed, sides of the breast. The potential for high resolution imaging of endogenous contrast, oxy and deoxy-hemoglobin, and, in the future, of targeted exogenous optical contrast agents warrants the substantial development and investigation that is proposed. This system brings the endogenous contrast imaging of S-PAT to practical test, coincident with state-of-the-art competitive and complimentary imaging modes, including US color flow Doppler imaging for comparison with S-PAT. The x-ray DTM system in the current BRP offers capabilities well beyond those of other research and clinical prototypes. The ultrasound in this combined system is meeting the goal of producing good images in essentially the same view as the x-rays and with good patient acceptance. Since the first submission of this renewal proposal, several concerns about the practical clinical performance of automated US scanning of the compressed breast have been investigated. They should be well resolved with the developments of a proposed tilting mesh compression paddle and an efficient acoustic coupling gel distribution system. With these further developments, the system will be ready to address a very serious question, the feasibility of using the first two modes of this system, DTM and automated US (AUS), for breast cancer screening. A large preliminary trial is proposed starting in the second year to demonstrate feasibility of frequent studies with the combined system and to evaluate the following questions in a callback-enriched screening study: 1) whether combined DTM/AUS will result in fewer callbacks than conventional mammography screening;and 2) whether the sensitivity of the combined system will increase significantly from the 72% historical rate for typical modern mammography practice. PUBLIC HEALTH RELEVANCE: The near future of breast imaging includes a 3D version of mammography (digital tomosynthesis mammography or DTM) in combination with ultrasound imaging. This project will marry DTM and mammography to automated ultrasound scanning and a new, optical imaging method "spectroscopic photoacoustic tomography", producing a combined system that will allow rapid comparison of any tissues in one image volume with the corresponding location in the other two image volumes. The system will be tested in simulated screening for provision of increased sensitivity to cancer with fewer unnecessary recalls for further imaging and biopsies.